VALPOIC ACID REDUCES THE INTRACELLULAR LEVEL OF GLUTATHIONE AND STIMULATES HUMAN-IMMUNODEFICIENCY-VIRUS

Modifications of the glutathione (GSH) intracellular level have been i mplicated in the regulation of human immunodeficiency virus (HIV) tran scription and expression. In regard to this hypothesis, we have invest igated the effects of valproic acid (VPA) on HIV replication. Indeed, it has been recently reported that VPA inhibits the human red blood ce ll glutathione reductase. In the supernatant of a CEM-SS T-lymphocytic cell line infected with the LAI strain of HIV-1, we observed an incre ase, in a dose-dependent fashion, of the reverse transcriptase activit y after treatment of cells with VPA. VPA also induced HIV expression i n the chronically infected monocytic U1 cell line which constitutively expresses low levels of virus, enhanced the HIV-long terminal repeat (LTR)-directed expression of beta-galactosidase in transiently transfe cted Jurkat T-cells, and potentiated the PMA effect on the LTR transac tivation. GSH assays showed that VPA treatment led to a decrease in th e intracellular level of this thiol compound in U937 (U1 parent-cell l ine) and in Jurkat T-cells. Work to understand the molecular mechanism of VPA-induced HIV transcription and expression are now in progress. VPA seems to be an adequate molecule to study the implications of a GS H decrease in the stimulation of HIV replication. However, a modificat ion of the intracellular balance between reduced and oxidized glutathi one, rather than a simple reduction of the intracellular glutathione l evel, could be of importance in the regulation of HIV replication and we are now testing this hypothesis. Finally, these findings already su ggest that VPA, which is an anticonvulsive drug frequently prescribed for the management of various seizure disorders, should not be recomme nded for treatment of epilepsy or other related illnesses in HIV-posit ive individuals.